Analgesic Agent

ABSTRACT

A pharmaceutical preparation useful for alleviating or treating a pain, e.g., a chronic pain (particularly, a neuropathic pain) is provided. The pharmaceutical preparation contains (a) a propionic acid-derived nonsteroidal anti-inflammatory agent (e.g., ibuprofen), (b) a non-pyrazolone antipyretic analgesic agent (e.g., acetaminophen), and (c) an opioid analgesic agent (e.g., codeine phosphate, dihydrocodeine phosphate). The pharmaceutical preparation may contain 5 to 100 parts by weight of the antipyretic analgesic agent (b) or 0.5 to 500 parts by weight of the analgesic agent (c) relative to 100 parts by weight of the anti-inflammatory agent (a). The pharmaceutical preparation may be substantially free from a nontoxic N-methyl-D-aspartate receptor antagonist and may contain 20 to 80 parts by weight of the antipyretic analgesic agent (b) and 1 to 100 parts by weight of the analgesic agent (c) relative to 100 parts by weight of the anti-inflammatory agent (a).

TECHNICAL FIELD

The present invention relates to a pharmaceutical preparation useful foralleviating (or mitigating) or treating a pain, for example, a chronicpain (particularly, a neuropathic pain).

BACKGROUND ART

Immediately alleviating a pain of which a patient with a disease ordisorder complains is most important to most of the treatment for thedisease or disorder in terms of the mitigation of the patient's physicalpain as well as mental anguish. Pain is usually classified into acutepain and chronic pain. The acute pain results from a tissue damagecaused by a stimulation such as a mechanical stimulus or heat.Heretofore, all of analgesic agents have been developed with the aim ofalleviating the acute pain. The chronic pain means that a paincontinuing for 6 or more months, which appears after a recovery of atissue damage resulting in acute pain or due to lumbago, migraine,arthritis, cancer, and other factors and hinders patient's daily life,or which results from an unknown origin. Moreover, pain is classifiedinto four categories according to the cause: nociceptive, inflammatory,neuropathic (or neurogenic), and psychogenic pains. These pains aretreated depending on the respective causes thereof. For example, theinvasive pain can completely subside by morphine or the like. Theinflammatory pain can cease after inhibition or elimination of the causeusing an anti-inflammatory agent. However, it is difficult to remove theneuropathic pain since the cause of the pain is specific. Specifically,the cause of the neuropathic pain is a temporary injury to the nervoussystem or an abnormal function of the nervous system. That is, the nerveitself has a trouble, and the plasticity in the nervous system becomeschronic. In addition, since the chronic pain induces a new plasticchange in the neural circuit, it is difficult to remit the symptom, tosay nothing of the cause. The neuropathic pain is a pain as representedby a sensuous expression such as “numbness” or “a shooting pain” and isalso a continuous or sudden pain. Moreover, the neuropathic pain isknown for its resistance to an antiphlogistic analgesic agent or anarcotic analgesic agent.

The effective method for treating the neuropathic pain includes, forexample, methods described in Folia Pharmacol. Jpn., 122, 192-200 (2003)(Non-patent Document 1). In this document, treatments with an α2adrenergic receptor antagonist, a sodium receptor antagonist, acapsaicin cream, a TrkB receptor inhibitor, or an Rho inhibitor havebeen examined.

Moreover, Japanese Patent Application Laid-Open No. 535833/2003(JP-2003-535833A, Patent Document 1) discloses that a pharmaceuticalcomposition containing a kappa-opioid (nalbuphine) and an opioidantagonist (naloxone, naltrexone, nalmefene) is useful for treating apain including both inflammatory and neuropathic pains. Incidentally,the document does not disclose that a propionic acid-derivednonsteroidal anti-inflammatory agent and a non-pyrazolone antipyreticanalgesic agent is further added or mixed to or with the pharmaceuticalcomposition.

Further, Japanese Patent Application Laid-Open No. 512081/1999(JP-11-512081A, Patent Document 2) discloses that a pharmaceuticalcomposition containing an opioid analgesic agent (such as codeine ordihydrocodeine) as a first component, a nonopioid analgesic agent (suchas acetaminophen or ibuprofen) as a second component, anN-methyl-D-aspartate receptor antagonist (such as dextromethorphan) as athird component is useful for treating an acute or chronic pain (e.g.,arthritic pain, lumbosacral, musculoskeletal pain, post-operative pain,and headache).

As described above, a variety of treatments for pain has been carriedout. However, preparations or treatment methods which enable moreeffective alleviation and treatment for pain is desired still now. Inparticular, there are few reports concerning effective treatment methodsfor a neuropathic pain, which is one of chronic pains, and thedevelopment of methods for treating the neuropathic pain effectively hasbeen desired.

[Patent Document 1] JP-2003-535833A (Claims 1, 8, and 9, paragraphnumber [0002])

[Patent Document 2] JP-11-512081A (Claims 1 and 15, page 8, lines 27-28of Specification)

[Non-patent Document 1] Folia Pharmacol. Jpn. 122, 192-200 (2003),attributed to Ueda Hiroshi

DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention

It is therefore an object of the present invention to provide apharmaceutical preparation (an analgesic agent) useful for alleviatingor treating a pain, for example, a chronic pain (particularly, aneuropathic pain), effectively.

Another object of the present invention is to provide a pharmaceuticalpreparation useful for treating a disease with a neuropathic pain and aneuropathic pain thereof (for example, carcinomatous pain, postherpeticneuralgia, post-thoracotomy pain, trigeminal neuralgia, phantom limbpain, causalgia, diabetic neuropathic pain, and injury or amputation oflimb).

Means to Solve the Problems

The inventors of the present invention made intensive studies to achievethe above objects and finally found that combination of a propionicacid-derived nonsteroidal anti-inflammatory agent, a non-pyrazoloneantipyretic analgesic agent, and an opioid analgesic agent potentiatesthe analgesic effect of the opioid analgesic agent, whereby even aneuropathic pain is effectively alleviated. The present invention wasaccomplished based on the above findings.

That is, the pharmaceutical preparation of the present inventioncontains a propionic acid-derived nonsteroidal anti-inflammatory agent(or a propionic acid-derivative nonsteroidal anti-inflammatory agent), anon-pyrazolone antipyretic analgesic agent, and an opioid analgesicagent. The proportion of the non-pyrazolone antipyretic analgesic agentmay be about 5 to 100 parts by weight relative to 100 parts by weight ofthe propionic acid-derived nonsteroidal anti-inflammatory agent. Theproportion of the opioid analgesic agent may be about 0.5 to 500 partsby weight relative to 100 parts by weight of the propionic acid-derivednonsteroidal anti-inflammatory agent. The proportion of the opioidanalgesic agent may be about 1 to 1000 parts by weight relative to 100parts by weight of the non-pyrazolone antipyretic analgesic agent. Thepharmaceutical preparation of the present invention may be substantiallyfree from a nontoxic N-methyl-D-aspartate receptor antagonist, and maycontain about 20 to 80 parts by weight of the non-pyrazolone antipyreticanalgesic agent and about 1 to 100 parts by weight of the opioidanalgesic agent relative to 100 parts by weight of the propionicacid-derived nonsteroidal anti-inflammatory agent.

The propionic acid-derived nonsteroidal anti-inflammatory agent to beused may include at least one member selected from the group consistingof ibuprofen, ketoprofen, flurbiprofen, flurbiprofen axetil, oxaprozin,fenoprofen, tiaprofenic acid, naproxen, pranoprofen, loxoprofen,alminoprofen, zaltoprofen, and a salt thereof. At least one memberselected from the group consisting of acetaminophen, dimetotiazinemesilate, and a salt thereof may be used as the non-pyrazoloneantipyretic analgesic agent. The opioid analgesic agent may include atleast one member selected from the group consisting of alfentanil,morphine, heroin, levorphanol, hydromorphone, oxymorphone, levellorphan,fentanyl, safentanyl, methadone, meperidine, cocaine, codeine, codeinephosphate, dihydrocodeine, dihydrocodeine phosphate, oxycodone, drocode,tramadol, nalbuphine, nalmefene, nalorphine, naloxone, naltrexone,hydrocodone, hydromorphone, propoxyphene, buprenorphine, butorphanol,pentazocine, and a salt thereof. Among them, for example, ibuprofen asthe propionic acid-derived nonsteroidal anti-inflammatory agent,acetaminophen as the non-pyrazolone antipyretic analgesic agent, andcodeine phosphate and/or dihydrocodeine phosphate as the opioidanalgesic agent may be combined.

The pharmaceutical preparation of the present invention is useful foralleviating (or mitigating) or treating a pain, for example, a chronicpain (particularly, a neuropathic pain) effectively.

Moreover, the pharmaceutical preparation of the present invention isused for alleviating or treating a neuropathic pain, containssubstantially no nontoxic N-methyl-D-aspartate receptor antagonist, andcontains a propionic acid-derived nonsteroidal anti-inflammatory agent,a non-pyrazolone antipyretic analgesic agent, and an opioid analgesicagent.

EFFECTS OF THE INVENTION

The pharmaceutical preparation (pharmaceutical composition) of thepresent invention can treat or alleviate patient's pain, for example, achronic pain (particularly, an intractable neuropathic pain) since inthe pharmaceutical preparation the propionic acid-derived nonsteroidalanti-inflammatory agent and the non-pyrazolone antipyretic analgesicagent potentiates the analgesic effect of the opioid analgesic agent.Further, the pharmaceutical preparation of the present invention is alsouseful for treating or curing a neuropathic pain and a diseasetherewith, for example, carcinomatous pain, postherpetic neuralgia,post-thoracotomy pain, trigeminal neuralgia, phantom limb pain,causalgia, diabetic neuropathic pain, and injury or amputation of limb.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 is a graph showing a change with passage of time of a pseudo painresponse-related latent period in Test Example 1.

DETAILED DESCRIPTION OF THE INVENTION Pharmaceutical Preparation

The pharmaceutical preparation of the present invention contains (a) apropionic acid-derived nonsteroidal anti-inflammatory agent, (b)anon-pyrazolone antipyretic analgesic agent, and (c) an opioid analgesicagent. The propionic acid-derived nonsteroidal anti-inflammatory agent(a) and the non-pyrazolone antipyretic analgesic agent (b) act aspotentiators for the opioid analgesic agent (c) and potentiate theanalgesic effect of the opioid analgesic agent (c).

(Propionic Acid-Derived Nonsteroidal Anti-Inflammatory Agent (a))

The propionic acid-derived nonsteroidal anti-inflammatory agent(hereinafter, sometimes abbreviated as the anti-inflammatory agent (a))means a compound which is one of nonsteroidal anti-inflammatory agentsand is derived from propionic acid. Examples of the anti-inflammatoryagent (a) may include ibuprofen, ketoprofen, flurbiprofen,flurbiprofenaxetil, oxaprozin, fenoprofen, tiaprofenic acid, naproxen,pranoprofen, loxoprofen, alminoprofen, zaltoprofen, a prodrug thereof, asalt thereof, and others. These anti-inflammatory agents (a) may be usedsingly or in combination. The preferred anti-inflammatory agent (a)includes ibuprofen. Ibuprofen is a substance having a chemical name,2-(4-isobutylphenyl)propionic acid, and is an active ingredientcontained in the Japanese Pharmacopoeia the 14^(th) edition(hereinafter, referred to as the “Japanese Pharmacopoeia”) and the like.

(Non-Pyrazolone Antipyretic Analgesic (b))

The non-pyrazolone antipyretic analgesic agent (hereinafter, sometimesabbreviated as the antipyretic analgesic (b)) may include acetaminophen,dimetotiazine mesilate, a prodrug thereof, a salt thereof, and others.These antipyretic analgesic agents (b) may be used singly or incombination. The preferred antipyretic analgesic agent (b) includesacetaminophen. Acetaminophen is a substance having a chemical name,N-(4-hydroxyphenyl)acetamide, and is an active ingredient contained inthe Japanese Pharmacopoeia and the like.

In the pharmaceutical preparation of the present invention, theproportion of the non-pyrazolone antipyretic analgesic agent (b) (forexample, acetaminophen) relative to 100 parts by weight of the propionicacid-derived nonsteroidal anti-inflammatory agent (a) (for example,ibuprofen) is not particularly limited to a specific one as long as theproportion is selected from the range of 5 to 100 parts by weight. Theproportion is usually about 10 to 90 parts by weight (e.g., about 20 to80 parts by weight), preferably about 30 to 70 parts by weight (e.g.,about 35 to 65 parts by weight), more preferably about 40 to 60 parts byweight (e.g., about 45 to 55 parts by weight), and particularlypreferably about 40 to 50 parts by weight.

(Opioid Analgesic Agent (c))

The opioid analgesic agent (hereinafter, sometimes abbreviated as theanalgesic agent (c)) may include alfentanil, morphine, heroin,levorphanol, hydromorphone, oxymorphone, levellorphan, fentanyl,safentanyl, methadone, meperidine, cocaine, codeine, codeinephosphate,dihydrocodeine, dihydrocodeine phosphate, oxycodone, drocode, tramadol,nalbuphine, nalmefene, nalorphine, naloxone, naltrexone, hydrocodone,hydromorphone, propoxyphene, buprenorphine, butorphanol, pentazocine, aprodrug thereof, a salt thereof, and others. These analgesic agents (c)may be used singly or in combination. The preferred analgesic agent (c)includes codeine phosphate and dihydrocodeine phosphate. Codeinephosphate is a substance having a chemical name,(5R,6S)-7,8-didehydro-4,5-epoxy-3-methoxy-17-methylmorphinan-6-olmonophosphate hemihydrate, and dihydrocodeine phosphate is a substancehaving a chemical name,(5R,6S)-4,5-epoxy-3-methoxy-17-methylmorphinan-6-ol monophosphate. Bothsubstances are active ingredients contained in the JapanesePharmacopoeia and the like.

The proportion of the opioid analgesic agent (c) (for example, at leastone member selected from the group consisting of codeine phosphate anddihydrocodeine phosphate) relative to 100 parts by weight of thepropionic acid-derived nonsteroidal anti-inflammatory agent (a) (forexample, ibuprofen) is not particularly limited to a specific one aslong as the proportion is selected from the range of 0.5 to 500 parts byweight. The proportion is usually about 1 to 500 parts by weight (e.g.,about 2 to 300 parts by weight), preferably about 1 to 400 parts byweight (e.g., about 3 to 200 parts by weight), more preferably about 1to 100 parts by weight (e.g., about 5 to 50 parts by weight), andparticularly preferably about 3 to 40 parts by weight (e.g., about 5 to30 parts by weight).

The proportion of the opioid analgesic agent (c) (for example, at leastone member selected from the group consisting of codeine phosphate anddihydrocodeine phosphate) relative to 100 parts by weight of thenon-pyrazolone antipyretic analgesic (b) (for example, acetaminophen)may be, for example, about 1 to 1000 parts by weight (e.g., about 2 to500 parts by weight), preferably about 3 to 200 parts by weight (e.g.,about 5 to 100 parts by weight), and more preferably about 4 to 150parts by weight (e.g., about 10 to 75 parts by weight).

A combination of the above-mentioned active ingredients (theanti-inflammatory agent (a), the antipyretic analgesic agent (b), andthe analgesic agent (c)) in the present invention is not particularlylimited to a specific one. Each active ingredient of the combination maybe a compound or a plurality of compounds selected from the examplesmentioned above. In particular, the following combination is preferred:a combination of ibuprofen as the anti-inflammatory agent (a),acetaminophen as the antipyretic analgesic agent (b), and codeinephosphate and/or dihydrocodeine phosphate as the analgesic agent (c).

The anti-inflammatory agent (a), antipyretic analgesic agent (b), andanalgesic agent (c) may include a mode of an optical isomer (forexample, R-body and S-body) or a mode of a mixture of the isomer(forexample, a racemic body, an enantiomer mixture, and a diastereomermixture). The above-mentioned proportion means a proportion of theanti-inflammatory agent (a), the antipyretic analgesic agent (b), andthe analgesic agent (c) which are not optically resolved (are racemicbodies). Therefore, use of a pharmaceutically active optical isomerneeds an adjustment of the above-mentioned proportion. For example, inthe case of use of a pharmaceutically active optical isomer of ibuprofen(e.g., S-ibuprofen) instead of a racemic body of ibuprofen as theanti-inflammatory agent (a), 0.5 part by weight of the optical isomercorresponds to 1 part by weight of the racemic body of ibuprofen.Accordingly, in the case of use of S-ibuprofen as the anti-inflammatoryagent (a), the proportion of the antipyretic analgesic agent (b)relative to the anti-inflammatory agent (a) and that of the analgesicagent (c) relative to the anti-inflammatory agent (a) correspond toabout twice of the above-mentioned ranges, respectively.

A variety of physiologically or pharmaceutically acceptable salts may beused as the salts of the above-mentioned active ingredients (theanti-inflammatory agent (a), the antipyretic analgesic agent (b), andthe analgesic agent (c)). An acid or base forming the salt may beselected according to the species of these active ingredients. Thesesalts may include, for example, an inorganic acid salt (e.g., a saltwith an acid such as hydrochloric acid, hydrobromic acid, sulfuric acid,nitric acid, or phosphoric acid); an organic acid salt [for example, asalt with a carboxylic acid {e.g., a salt with a monocarboxylic acid(e.g., a salt with an acid such as oxalic acid, acetic acid,trichloroacetic acid, or trifluoroacetic acid), a polycarboxylic acidsalt (e.g., a salt with an acid such as succinic acid, maleic acid, orfumaric acid), and a hydroxycarboxylic acid salt (e.g., a salt with anacid such as tartaric acid, citric acid, lactic acid, gluconic acid,salicylic acid, phenolphthalin, or tannic acid)}, an amino acid salt(e.g., aspartate), and an organic sulfonic acid salt {e.g., a salt of analkanesulfonic acid (e.g., a salt of an acid such as methanesulfonicacid or ethanesulfonic acid), and an arenesulfonic acid salt (e.g., asalt of an acid such as benzenesulfonic acid, toluenesulfonic acid, ordiphenyldisulfonic acid)}]; a salt of an inorganic base [for example, asalt of an alkali metal hydroxide (e.g., a salt of a hydrate such assodium hydroxide or potassium hydroxide), an alkali metal carbonate, asalt of an alkaline earth metal hydroxide (e.g., a salt of a hydroxidesuch as calcium hydroxide or magnesium hydroxide), an alkaline earthmetal carbonate, an aluminum salt, and an ammonium salt]; and a salt ofan organic base [for example, an alkylamine salt (e.g., a trimethylaminesalt and a triethylamine salt), an alkanolamine salt (e.g., amonoethanolamine salt and a triethanolamine salt), a polyamine salt suchas an alkylenediamine, and a tertiary amine salt such as a pyridinesalt].

Moreover, the anti-inflammatory agent (a), the antipyretic analgesicagent (b), and the analgesic agent (c) also include a hydrous compound(or a hydrate) in addition to the physiologically or pharmaceuticallyacceptable salt.

(Other Active Ingredients)

In addition to the above-mentioned anti-inflammatory agent (a),antipyretic analgesic agent (b), and analgesic agent (c), thepharmaceutical preparation of the present invention may suitably containother active ingredients which can be added to an analgesic agent. Theactive ingredient is not particularly limited to a specific one as longas the active ingredient has no adverse effect on the analgesic effectsand safety of the pharmaceutical preparation of the present invention.Incidentally, the pharmaceutical preparation of the present inventionusually contains substantially no nontoxic N-methyl-D-aspartate (NMDA)receptor antagonist (particularly, dextromethorphan or a salt thereof).

The NMDA receptor includes all of the binding site subcategoriesassociated with the NMDA receptor (for example, the glycine-biding siteand the phenylcyclidine (PCP)-binding site), and the NMDA channel (forexample, the magnesium channel and the calcium channel). The nontoxicNMDA receptor antagonist means a nontoxic substance that can block anNMDA receptor binding site or a NMDA channel. The nontoxic NMDA receptorantagonist may include, for example, dextromethorphan, dextrorphan,ketamine, memantine, pyrroloquinoline quinone,cis-4-(phosphonomethyl)-2-piperidine carboxylic acid, and aphysiologically or pharmaceutically acceptable salt thereof (forexample, physiologically or pharmaceutically acceptable salts of theanti-inflammatory agent (a), antipyretic analgesic agent (b), andanalgesic agent (c)).

Other active ingredients are not particularly limited to a specific oneas long as the ingredients do not adversely affect on the analgesiceffects and safety of the pharmaceutical preparation of the presentinvention. For example, other active ingredients may include activeingredients described in Appendix 1 of “Standards of Approval for themanufacture (import) of Antipyretic analgesics” on over-the-counterdrugs [Drugs in Japan, OTC Drugs, 2002-03, the 13th edition, Jiho, Inc.,pages 92 to 94, issued on Jul. 30, 2001] and active ingredientsdescribed in Appendix 1 of “Standards of Approval for the manufacture(import) of Cold medicines” on over-the-counter drugs [Drugs in Japan,OTC Drugs, 2002-03, the 13th edition, Jiho, Inc., pages 1 to 4, issuedon Jul. 30, 2001].

In addition to those based on the above-mentioned Standards of Approval,usually, active ingredients suitable for analgesic application may alsobe added or mixed to or with the pharmaceutical preparation of thepresent invention as long as the active ingredients have no adverseeffect on the analgesic effects and safety of the pharmaceuticalpreparation of the present invention.

Such an active ingredient may include, for example, a vitamin (e.g., afat-soluble vitamin such as vitamin A, D, E, K, or U; and awater-soluble vitamin such as vitamin B, C, or P), an antipyreticanalgesic anti-inflammatory agent (e.g., a pyrazolone antipyreticanalgesic agent such as sulpyrine; a salicylic acid-based agent (asalicylic acid derivative) such as sodium salicylate or aspirin, afenamic acid-based agent (a fenamic acid derivative) such as flufenamicacid or mefenamic acid, an arylacetic acid-based agent (an arylaceticacid derivative) such as diclofenac sodium or indometacin, apyrazolidine-based agent (a pyrazolidine derivative) such asphenylbutazone or oxyphenylbutazone, a pyrimidine-based agent (apyrimidine derivative) such as bucolome, an oxicam-based agent (anoxicam derivative) such as piroxicam, and isopropylantipyrine), anantihistamine (e.g., clemastine fumarate, diphenhydramine hydrochloride,and chlorpheniramine maleate), an antitussive expectorant (for example,an antitussive such as chloperastine, dextromethorphan, or benzonatate;an expectorant, e.g., a mucolytic agent such as bromhexinehydrochloride, L-cysteinehydrochloride, L-cysteinemethylhydrochloride,or acetylcysteine, a mucous repair agent such as carbocisteine, and amucous lubrication agent such as ambroxol hydrochloride), abronchodilator or an antasthmatic agent (for example, a β₂-adrenoceptorstimulant such as pseudoephedorine, ephedrine hydrochloride,methylephedrine hydrochloride, terbutaline hydrochloride, isoproterenol,salbutamol, or terbutaline, a xanthine-based agent (a xanthinederivative) such as theophylline, aminophylline, or proxyphylline, andcromoglicic acid), a local anesthetic agent (for example, an alkamineaminobenzoate-based agent (an alkamine aminobenzoate derivative) such astetracaine hydrochloride or procaine hydrochloride; a dibucaine-basedagent (a dibucaine derivative) such as dibucaine hydrochloride; and axylidine-based agent (a xylidine derivative) such as bupivacainehydrochloride, mepivacaine hydrochloride, lidocaine hydrochloride, orropivacaine hydrochloride), a caffeine compound, an antacid, an aminoacid compound, and a crude drug. These active ingredients may be usedsingly or in combination. Among these ingredients, the local anestheticagent is often mixed as other active ingredients. The amount of thelocal anesthetic agent to be mixed in a dose of the pharmaceuticalpreparation of the present invention may be selected from the range ofabout 0.1 to 500 mg depending on the species thereof and may usually beabout 1 to 400 mg (for example, about 2 to 300 mg). The amount of thelocal anesthetic agent to be mixed in a dose of the pharmaceuticalpreparation of the present invention is not particularly limited to aspecific one and may be as follows: the amount of tetracainehydrochloride is about 6 to 80 mg, the amount of procaine hydrochlorideis about 10 to 1000 mg, the amount of dibucaine hydrochloride is about 3to 9 mg, the amount of bupivacaine hydrochloride is about 2.5 to 100 mg,the amount of mepivacaine hydrochloride is about 10 to 500 mg, theamount of lidocaine hydrochloride is about 10 to 300 mg, or the amountof ropivacaine hydrochloride is about 8 to 20 mg.

The pharmaceutical preparation of the present invention can beadministered orally or parenterally (for example, transdermally,intravenously, and intramuscularly) according to the symptom (or state)of a patient with a pain. For example, it is preferable that thepharmaceutical preparation of the present invention be orallyadministered to a patient with a chronic pain, particularly, aneuropathic pain. The preparation suitable for oral administration maybe a solid preparation (for example, tablets, pills, microfine particlesor powders, granules, powders, hard capsules, soft capsules, troches,and dry syrups) or a non-solid preparation (for example, syrups, liquidsand solutions, and suspensions). Incidentally, the pharmaceuticalpreparation may also include a preparation in which the activeingredient has a controlled releasability (for example, a rapid-releasepreparation and a sustained release preparation).

The pharmaceutical preparation of the present invention may be obtainedby preparing the anti-inflammatory agent (a), the antipyretic analgesicagent (b) and the analgesic agent (c) in combination with a carrier (anadditive suitable for a pharmaceutical preparation) with a conventionalpreparation manner. That is, the pharmaceutical preparation of thepresent invention may be produced, for example, according to productionprocesses of tablets, granules, powders, hard capsules, soft capsules,troches, dry syrups, syrups, liquids and solutions, and suspensionsdescribed in the Japanese Pharmacopoeia. Incidentally, the solidpreparation may usually be prepared by using at least one carrierselected from the group consisting of a binder, an excipient, and adisintegrant (particularly, at least an excipient). For example, thegranules may be prepared by granulating the active ingredients andcarrier component through extrusion granulation or spray granulation,and if necessary, sizing the resultant. The tablets may be produced bymixing the granules and an additive and compression molding tablets fromthe mixture, and if necessary, coating the tablets for masking the tasteor imparting enteric property or prolonged action thereto with per seknown methods. The capsules may be prepared by filling granules in acapsule. The liquids and solutions may be prepared, depending on thedosage form, by mixing the active ingredients and a liquid carriercomponent (e.g., water), and if necessary, an additive (for example, anemulsifier, a dispersing agent or a suspending agent, a preservative, astabilizer, a corrigent, and a pH adjusting agent or a buffer). Ifnecessary, the liquids and solutions are sterilized.

The above-mentioned carrier (additive for the preparation) may includean additive commonly used for manufacturing a pharmaceutical preparationhaving the above-mentioned dosage form. For example, the carrier mayinclude an excipient, a binder, a disintegrant, a lubricant, and acoating agent each of which is listed in the Japanese Pharmacopoeia and“Encyclopedia of Pharmaceutical Excipients (Iyakuhin Tenkabutsu Jiten)”(Yakuji Nippo Ltd., the second issue, issued on Mar. 25, 2002).

Among the carrier components or additives, the excipient may include astarch such as a corn starch, a polysaccharide such as a crystallinecellulose; a saccharide such as lactose, white soft sugar or refinedsugar, glucose, mannitol, or sorbitol; and others. The binder mayinclude a polysaccharide such as a pregelatinized starch, agar, gumacacia (or gum arabic), or dextrin; a synthetic polymer such as apolyvinylpyrrolidone, a polyvinyl alcohol, a carboxyvinyl polymer, or apolylactic acid; a cellulose ether such as a methyl cellulose, an ethylcellulose, a carboxymethyl cellulose (CMC) sodium, a hydroxyethylcellulose, a hydroxypropyl cellulose, or a hydroxypropylmethylcellulose; and others. The disintegrant may include calcium carbonate, acarboxymethyl cellulose calcium (a carmellose calcium), a crosslinkedpovidone, a low-substituted hydroxypropyl cellulose, and others. Thelubricant may include, for example, a talc, magnesium stearate, and apolyethylene glycol 6000. Moreover, a disintegrant aid, a lipid (forexample, a fat and oil such as a hydrogenated vegetable oil, and aphospholipid), a macrogol, a corrigent or a masking agent, a coloringagent, an aromatic substance, and others may be used.

The coating agent which may be used may include, for example, asaccharide, a cellulose derivative such as an ethyl cellulose or ahydroxymethyl cellulose, a polyoxyethylene glycol, a cellulose acetatephthalate, a hydroxypropylmethyl cellulose phthalate, and eudragit(e.g., a methacrylic acid-acrylic acid copolymer). The coating agent maybe an enteric component such as a hydroxypropylmethyl cellulosephthalate or a gastric soluble component comprising a polymer (e.g.,eudragit) containing a basic component such as adialkylaminoalkyl(meth)acrylate.

The pharmaceutical preparation of the present invention is effective intreating or alleviating pain. Although the pain is not particularlylimited to a specific one, the pain is roughly divided into acute painand chronic pain. The pain is also divided into four followingcategories according to the causes: nociceptive, inflammatory,neuropathic, and psychogenic pains. The pharmaceutical preparation ofthe present invention is effective for the chronic pain among others, inparticular, for a neuropathic pain accompanied by a disorder of thenerve itself. Further, the pharmaceutical preparation of the presentinvention is effective for carcinomatous pain, post-herpes-zosterneuralgia, post-thoracotomy pain, trigeminal neuralgia, phantom limbpain, causalgia, diabetic neuropathic pain, injury or amputation oflimb, and others, each of which is a disease with a neuropathic pain.

Furthermore, the pharmaceutical preparation of the present invention hasan excellent enough analgesic effect, also an excellent analgesic effecton a neuropathic pain, compared with an analgesic effect of the opioidanalgesic agent (analgesic agent (c)) alone.

Neither the propionic acid-derived nonsteroidal anti-inflammatory agentnor the non-pyrazolone antipyretic analgesic agent has an analgesiceffect on a neuropathic pain. However, in a combination use with theopioid analgesic agent, a combination of the propionic acid-derivednonsteroidal anti-inflammatory agent and the non-pyrazolone antipyreticanalgesic agent serves as the potentiator for the analgesic effect ofthe opioid analgesic agent. Thus the pharmaceutical preparation of thepresent invention shows an excellent analgesic effect on the neuropathicpain.

The pharmaceutical preparation of the present invention is usuallyadministered (for example, orally administered) in one to severaldose(s) a day. The dose thereof may suitably be adjusted depending onthe age, body weight, symptom, and others of a subject [human beings(including infants), non-human beings (e.g., mammals such as bovines,monkeys, dogs, or cats)].

In the pharmaceutical preparation of the present invention, theanti-inflammatory agent (a) (e.g., ibuprofen) is preferably used so thatthe dose of the anti-inflammatory agent (a) (e.g., ibuprofen) can beabout 100 to 1000 mg/day, preferably about 200 to 800 mg/day, and morepreferably about 300 to 600 mg/day in adult.

Moreover, in the pharmaceutical preparation of the present invention,the amount of the antipyretic analgesic agent (b) (e.g., acetaminophen)may be adjusted depending on the used amount of the anti-inflammatoryagent (a) (e.g., ibuprofen). The antipyretic analgesic agent (b) (e.g.,acetaminophen) may be used in a proportion of about 40 to 60 parts byweight, preferably about 40 to 50 parts by weight, relative to 100 partsby weight of the anti-inflammatory agent (a) (e.g., ibuprofen).

Further, in the pharmaceutical preparation of the present invention, theamount of analgesic agent (c) (e.g., at least one member selected fromthe group consisting of codeine phosphate and dihydrocodeine phosphate)may be adjusted depending on the used amount of the anti-inflammatoryagent (a) (e.g., ibuprofen). The analgesic agent (c) (e.g., at least onemember selected from the group consisting of codeine phosphate anddihydrocodeine phosphate) may be mixed in a proportion of about 1 to 500parts by weight, preferably about 1 to 100 parts by weight, relative to100 parts by weight of the anti-inflammatory agent (a) (e.g.,ibuprofen).

The pharmaceutical preparation of the present invention may contain alocal anesthetic agent in addition to the anti-inflammatory agent (a),the antipyretic analgesic agent (b), and the analgesic agent (c). Theused amount of the local anesthetic agent may be adjusted depending onthe used amount of the anti-inflammatory agent (a) (e.g., ibuprofen).The local anesthetic agent may be used in a proportion of about 0.1 to200 parts by weight, preferably about 0.5 to 100 parts by weight (e.g.,about 1 to 70 parts by weight), relative to 100 parts by weight of theanti-inflammatory agent (a) (e.g., ibuprofen).

INDUSTRIAL APPLICABILITY

The pharmaceutical preparation of the present invention is effective fortreating or alleviating a pain such as acute pain or chronic pain (forexample, nociceptive, inflammatory, neuropathic, and psychogenic pains).The pharmaceutical preparation of the present invention also has abeneficial effect on a neuropathic pain accompanied by a disorder of thenerve itself or a disease resulting from a neuropathic pain (forexample, carcinomatous pain, postherpetic neuralgia, post-thoracotomypain, trigeminal neuralgia, phantom limb pain, causalgia, diabeticneuropathic pain, and injury or amputation of limb).

EXAMPLES

Hereinafter, the following examples are intended to describe thisinvention in further detail and should by no means be interpreted asdefining the scope of the invention.

Test Example 1 Dihydrocodeine Phosphate Analgesic Effect on ChronicConstriction Injury (CCI) Model

The three following agents (1) to (3) were used as test agents: (1) acombination agent containing ibuprofen and acetaminophen in a weightratio of ibuprofen:acetaminophen which was 1:0.5 (hereinafter, sometimesreferred to as the “two-component combination agent”; ComparativeExample 1), (2) a combination agent containing ibuprofen, acetaminophen,and dihydrocodeine phosphate in a weight ratio ofibuprofen:acetaminophen:dihydrocodeine phosphate which was 1:0.5:0.06(hereinafter, sometimes referred to as the “three-component combinationagent”; Example 1), and (3) dihydrocodeine phosphate (DCP) alone(Comparative Example 2). The analgesic effects of these agents weretested using Plantar test in accordance with the method of Bennett andXie [Bennett G J and Xie Y-K: A peripheral mononeuropathy in rat thatproduces disorders of pain sensation like those seen in man. Pain, 33(1988) 87-107]. Incidentally, a group administered 1% carboxymethylcellulose sodium (1% CMC—Na) alone was used as a control group.

Specifically, CCI model rats were made in accordance with the method ofBennett et al. and the method of Yamamoto et al. [Yamamoto T and Yaksh TL: Spinal pharmacology of thermal hyperesthesia induced by incompleteligation of sciatic nerve. Anesthesiology 75, 817-826 (1991)]. Then eachtest agent was orally administered at a dose of 5 mL/kg to the rats. ThePlantar test was performed every 30 minutes from the start of theadministration to 3 hours after the administration to measure a pseudopain response-related withdrawal latency (second) of the rat hind limbwhich had undergone C+CI. The results are shown in Table 1.Incidentally, in FIG. 1, white bars, black bars, horizontal-stripedbars, and vertical-striped bars correspond to the control group,Comparative Example 1, Comparative Example 2, and Example 1,respectively.

TABLE 1 Pseudo Pain Response-Related Withdrawal Latency in Rats (unit:second) Before After After After After After After Administration 30minutes 1 hour 1.5 hours 2 hours 2.5 hours 3 hours Control Group 7.3 7.46.8 6.7 6.2 6.5 5.3 (CMC-Na administration) Comparative Example 1 7 86.1 7.5 7.6 7.1 7.4 (2-component combination agent administration)Comparative Example 2 6.5 11.6 9.8 6.8 6.9 8.1 8.9 (DCP administration)Example 1 7 15.9 11.6 14 14.6 15.3 15.4 (3-component combination agentadministration)

As apparent from Table 1 and FIG. 1, in the case of the administrationof the two-component combination agent, no analgesic effect onneuropathic pain was observed. In the case of the administration ofdihydrocodeine phosphate alone, an analgesic effect similar to the caseof the two-component combination agent or only slight analgesic effectwas recognized. In contrast, in the case of the three-componentcombination agent, in which dihydrocodeine phosphate had been added tothe two-component combination agent, an excellent analgesic effect wasobserved compared with the administration of dihydrocodeine phosphatealone.

Preparation Example 1

Formulation per tablet (total amount 140 mg): ibuprofen 75 mg,acetaminophen 32.5 mg, codeine phosphate 8 mg, corn starch 17.5 mg, anda low-substituted hydroxypropylcellulose 7 mg

According to the above-mentioned formulation, tablets to be taken as twotablets at a time were produced in accordance with a known mannerdescribed in General Rules for Preparations of Japanese Pharmacopoeia.

Preparation Example 2

Formulation per tablet (total amount 140 mg): ibuprofen 60 mg,acetaminophen 30 mg, dihydrocodeine phosphate 4 mg, corn starch 39 mg,and a low-substituted hydroxypropylcellulose 7 mg

According to the above-mentioned formulation, tablets to be taken as twotablets at a time were produced in accordance with a known mannerdescribed in General Rules for Preparations of Japanese Pharmacopoeia.

Preparation Example 3

Formulation per capsule (total amount 170 mg): ibuprofen 75 mg,acetaminophen 32.5 mg, codeine phosphate 16 mg, corn starch 44.5 mg, andmagnesium stearate 2 mg

According to the above-mentioned formulation, capsules to be taken astwo capsules at a time were produced in accordance with a known mannerdescribed in General Rules for Preparations of Japanese Pharmacopoeia.

Preparation Example 4

Formulation per capsule (total amount 170 mg): ibuprofen 60 mg,acetaminophen 30 mg, dihydrocodeine phosphate 4 mg, corn starch 74 mg,and magnesium stearate 2 mg

According to the above-mentioned formulation, capsules to be taken astwo capsules at a time were produced in accordance with a known mannerdescribed in General Rules for Preparations of Japanese Pharmacopoeia.

Preparation Example 5

Formulation per package of granules (total amount 640 mg): ibuprofen 150mg, acetaminophen 65 mg, codeine phosphate 16 mg, lactose 154 mg,crystalline cellulose 200 mg, corn starch 50 mg, and a low-substitutedhydroxypropylcellulose 5 mg

According to the above-mentioned formulation, granules to be taken asone package at a time were produced in accordance with a known mannerdescribed in General Rules for Preparations of Japanese Pharmacopoeia.

Preparation Example 6

Formulation per package of granules (total amount 630 mg): ibuprofen 120mg, acetaminophen 30 mg, dihydrocodeine phosphate 8 mg, lactose 200 mg,crystalline cellulose 267 mg, and a low-substitutedhydroxypropylcellulose 5 mg

According to the above-mentioned formulation, granules to be taken asone package at a time were produced in accordance with a known mannerdescribed in General Rules for Preparations of Japanese Pharmacopoeia.

1. A pharmaceutical preparation containing a propionic acid-derived nonsteroidal anti-inflammatory agent, a non-pyrazolone antipyretic analgesic agent, and an opioid analgesic agent.
 2. A pharmaceutical preparation according to claim 1, wherein the proportion of the non-pyrazolone antipyretic analgesic agent is 5 to 100 parts by weight relative to 100 parts by weight of the propionic acid-derived nonsteroidal anti-inflammatory agent.
 3. A pharmaceutical preparation according to claim 1, wherein the proportion of the opioid analgesic agent is 0.5 to 500 parts by weight relative to 100 parts by weight of the propionic acid-derived nonsteroidal anti-inflammatory agent.
 4. A pharmaceutical preparation according to claim 1, wherein the proportion of the opioid analgesic agent is 1 to 1000 parts by weight relative to 100 parts by weight of the non-pyrazolone antipyretic analgesic agent.
 5. A pharmaceutical preparation according to claim 1, which is substantially free from a nontoxic N-methyl-D-aspartate receptor antagonist, wherein the proportion of the non-pyrazolone antipyretic analgesic agent and that of the opioid analgesic agent are 20 to 80 parts by weight and 1 to 100 parts by weight, respectively, relative to 100 parts by weight of the propionic acid-derived nonsteroidal anti-inflammatory agent.
 6. A pharmaceutical preparation according to claim 1, wherein the propionic acid-derived nonsteroidal anti-inflammatory agent comprises ibuprofen, the non-pyrazolone antipyretic analgesic agent comprises acetaminophen, and the opioid analgesic agent comprises at least one member selected from the group consisting of codeine phosphate and dihydrocodeine phosphate. 7-9. (canceled)
 10. A pharmaceutical preparation for alleviating or treating a neuropathic pain, which is substantially free from a nontoxic N-methyl-D-aspartate receptor antagonist and contains a propionic acid-derived nonsteroidal anti-inflammatory agent, a non-pyrazolone antipyretic analgesic agent, and an opioid analgesic agent.
 11. A method for alleviating or treating a pain by administrating a pharmaceutical preparation recited in claim
 1. 12. A method according to claim 11, wherein the pain is a chronic pain.
 13. A method according to claim 11, wherein the pain is a neuropathic pain. 